Reconstructed influenza A/H3N2 infection histories reveal variation in incidence and antibody dynamics over the life course

Humans experience many influenza infections over their lives, resulting in complex and varied immunological histories. Although experimental and quantitative analyses have improved our understanding of the immunological processes defining an individual's antibody repertoire, how these within-host processes are linked to population-level influenza epidemiology remains unclear. Here, we used a multi-level mathematical model to jointly infer antibody dynamics and individual-level lifetime influenza A/H3N2 infection histories for 1,130 individuals in Guangzhou, China, using 67,683 haemagglutination inhibition (HI) assay measurements against 20 A/H3N2 strains from repeat serum samples collected between 2009 and 2015. These estimated infection histories allowed us to reconstruct historical seasonal influenza patterns and to investigate how influenza incidence varies over time, space and age in this population. We estimated median annual influenza infection rates to be approximately 18% from 1968 to 2015, but with substantial variation between years. 88% of individuals were estimated to have been infected at least once during the study period (2009-2015), and 20% were estimated to have three or more infections in that time. We inferred decreasing infection rates with increasing age, and found that annual attack rates were highly correlated across all locations, regardless of their distance, suggesting that age has a stronger impact than fine-scale spatial effects in determining an individual's antibody profile. Finally, we reconstructed each individual's expected antibody profile over their lifetime and inferred an age-stratified relationship between probability of infection and HI titre. Our analyses show how multi-strain serological panels provide rich information on long term, epidemiological trends, within-host processes and immunity when analyzed using appropriate inference methods, and adds to our understanding of the life course epidemiology of influenza A/H3N2. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JAH is supported by a Wellcome Trust Early Career Award (grant 225001/Z/22/Z). This study was supported by grants from the NIH R56AG048075 (DATC, JL), NIH R01AI114703 (DATC, BY), and the Wellcome Trust 200861/Z/16/Z (SR) and 200187/Z/15/Z (SR). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ‐2021014 and 2019B121205009 (HZ). DATC, KOK, JL, JMR, and SR acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246 and R01AI160780). JMR acknowledges support from the Medical Research Council (MR/S004793/1; MR/V038613/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). KOK acknowledges support from Health and Medical Research Fund (reference numbers: INF-CUHK-1, 17160302, 18170312, 22210232, CID-CUHK-A, COVID1903008), General Research Fund (reference numbers: 14112818, 24104920), Group Research Scheme of The Chinese University of Hong Kong, and Funding Allocation to Faculties by Research Committee of The Chinese University of Hong Kong. The funders played no role in designing or carrying out the study. DATC declares research funding from Merck, Sharp and Dohme and from Pfizer for research unrelated to this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study protocols and instruments were approved by the following institutional review boards: Johns Hopkins Bloomberg School of Public Health, University of Hong Kong, Guangzhou No. 12 Hospital, and Shantou University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All code and data required to reproduce the analyses are available online at https://github.com/jameshay218/fluscape\_infection\_histories [https://github.com/jameshay218/fluscape\_infection\_histories][1] [1]: https://github.com/jameshay218/fluscape_infection_histories